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Original Research
PD-1, but not PD-L1, expressed by islet-reactive CD4+ T cells suppresses infiltration of the pancreas during Type 1 Diabetes
Kristen E. Pauken, Marc K. Jenkins, Miyuki Azuma and Brian T. Fife
Diabetes 2013 Apr; DB_121475. https://doi.org/10.2337/db12-1475
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Abstract

The inhibitory receptor PD-1 constrains Type 1 Diabetes (T1D) in the non-obese diabetic (NOD) mouse. However, how PD-1 influences diabetogenic CD4+ T cells during natural diabetes is not fully understood. To address this question we developed a novel model to investigate antigen-specific CD4+ T cells under physiological conditions in vivo. We transferred a low number of naïve CD4+ T cells from the BDC2.5 mouse into prediabetic NOD mice to mimic a physiological precursor frequency and allowed the cells to become primed by endogenous autoantigen. Transferred BDC2.5 T cells became activated, differentiated into T-bet+ IFNγ-producing cells, and infiltrated the pancreas. In this model, loss of PD-1, but not PD-L1, on the antigen-specific CD4+ T cell resulted in increased cell numbers in the spleen, pancreas-draining lymph node and pancreas. PD-1-deficiency also increased expression of the chemokine receptor CXCR3. Lastly, histological data showed that a loss of PD-1 caused BDC2.5 cells to penetrate deep into the islet core, resulting in conversion from peri-insulitis to destructive insulitis. These data support a model by which PD-1 regulates islet-reactive CD4+ T cells in a cell intrinsic manner by suppressing proliferation, inhibiting infiltration of the pancreas, and limiting diabetes.

Keywords
  • Diabetes
  • T cells
  • Autoimmunity
  • Tolerance
  • Transgenic/Knockout Mice
  • Received October 24, 2012.
  • Accepted March 21, 2013.
  • © 2013 by the American Diabetes Association.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

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Diabetes: 67 (5)

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May 2018
Volume 67, Issue 5

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PD-1, but not PD-L1, expressed by islet-reactive CD4+ T cells suppresses infiltration of the pancreas during Type 1 Diabetes
Kristen E. Pauken, Marc K. Jenkins, Miyuki Azuma, Brian T. Fife
Diabetes Apr 2013, DB_121475; DOI: 10.2337/db12-1475

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PD-1, but not PD-L1, expressed by islet-reactive CD4+ T cells suppresses infiltration of the pancreas during Type 1 Diabetes
Kristen E. Pauken, Marc K. Jenkins, Miyuki Azuma, Brian T. Fife
Diabetes Apr 2013, DB_121475; DOI: 10.2337/db12-1475
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Keywords

Diabetes
T cells
Autoimmunity
Tolerance
Transgenic/Knockout Mice

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